PHF6 and DNMT3A mutations are enriched in distinct subgroups of mixed phenotype acute leukemia with T-lineage differentiation

Abstract

The genetic aberrations that drive mixed phenotype acute leukemia (MPAL) remain largely unknown, with the exception of a small subset of MPALs harboring <i>BCR</i> <i>-ABL1</i> and <i>MLL</i> translocations. We performed clinicopathologic and genetic evaluation of 52 presumptive MPAL cases at Memorial Sloan Kettering Cancer Center. Only 29 out of 52 (56%) cases were confirmed to be bona fide MPAL according to the 2016 World Heath Organization classification. We identified <i>PHF6</i> and <i>DNMT3A</i> mutations as the most common recurrent mutations in MPAL, each occurring in 6 out of 26 (23%) cases. These mutations are mutually exclusive of each other and <i>BCR-ABL1</i>/<i>MLL</i> translocations. <i>PHF6</i>- and <i>DNMT3A</i>-mutated MPAL showed marked predilection for T-lineage differentiation (5/6 <i>PHF6</i> mutated, 6/6 <i>DNMT3A</i> mutated). <i>PHF6</i>-mutated MPAL occurred in a younger patient cohort compared with <i>DNMT3A</i>-mutated cases (median age, 27 years vs 61 years, <i>P</i> < .01). All 3 MPAL cases with both T- and B-lineage differentiation harbored <i>PHF6</i> mutations. MPAL with T-lineage differentiation was associated with nodal or extramedullary involvement (9/15 [60%] vs 0, <i>P</i> = .001) and a higher relapse incidence (78% vs 22%, <i>P</i> = .017) compared with those without T-lineage differentiation. Sequencing studies on flow-cytometry-sorted populations demonstrated that <i>PHF6</i> mutations are present in all blast compartments regardless of lineage differentiation with high variant allele frequency, implicating <i>PHF6</i> as an early mutation in MPAL pathogenesis. In conclusion, <i>PHF6</i> and <i>DNMT3A</i> mutations are the most common somatic alterations identified in MPAL and appear to define 2 distinct subgroups of MPAL with T-lineage differentiation with inferior outcomes.